As our population gets older, age related macular degeneration (AMD) will reach epidemic proportions in the United States. Therapies to date have focused on the anti-angiogenic therapy with mixed results. Recent studies would suggest that the immune system plays a significant role in the pathogenesis of AMD. The composition of drusen, one of the earliest clinical findings in AMD, have been extensively investigated. Complement, lipids, and lipoproteins B and E are commonly found in ocular drusen as they are in atherosclerotic plaques. Hageman et al have proposed that drusen are the product of a localized inflammatory response which would occur after retinal pigment epithelium injury. Recent reports have supported further the notion of the immune system playing a role (but yet to be fully defined) in AMD. The age related eye disease study (AREDS) evaluated the risk factors for the incidence of advanced age related macular degeneration and found that using anti-inflammatory medication significantly reduced (Odds Ratio 0.22, C.I. 0.08-0.59) the risk of developing the geographic atrophy form of AMD. Experimental models and patient material have, to date, suggested a role for macrophages and complement. We hypothesize that the underlying mechanism that leads to choroidal neovascularization (CNV) is similar to those at play in atherosclerosis. If this is the case, then CNV treatment should be amenable to new immunomodulatory agents directed against specific parts of the immune system. We investigated the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. This was a pilot, Phase I/II, prospective, randomized, unmasked, singlecenter trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 or 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of 5 injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion: These preliminary but proof of priniciple data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated. Newer approaches to immune therapy are being discussed and prepared